ACRT Journal

Introduction

Appendiceal neuroendocrine tumours are typically discovered incidentally in 0.3-0.9% of appendectomy specimens and are usually removed for acute appendicitis. These tumours are classified based on pathological features as well-differentiated neuroendocrine tumours (NETs), poorly differentiated neuroendocrine carcinomas (NECs) and mixed neuroendocrine and nonneuroendocrine neoplasms (MiNENs). The latter typically have a nonneuroendocrine mucinous component, which distinguishes them from MANEC (mixed adenoneuroendocrine carcinoma), in which the nonneuroendocrine component is typically poorly differentiated [1]. Since MiNENs are the rarest type of neuroendocrine appendiceal neoplasm, there are no standard guidelines for their diagnosis and treatment, as well as no clear surgical recommendations or universally recognized therapeutic regimens [2]. Therefore, expert and multidisciplinary management is strongly recommended to deal with the complexities of these ultrarare disease. Here, we present a case report of a patient with pelvic MiNEN who underwent surgical resection and treatment via a polypharmacological approach. The administered treatments included HIPEC (intraperitoneal intraoperative hyperthermia), oral chemotherapy and somatostatin analogues. This report aims to provide a comprehensive description of the multidisciplinary management and outcomes of this patient.

Case Description

In October 2020, a 41-year-old woman who desired pregnancy underwent medical investigation and imaging assessments to determine the cause of her infertility. An ultrasound (US) scan revealed a massive lesion in the left ovary that was suspicious for malignancy. As a result, contrast-enhanced pelvic magnetic resonance imaging (MRI) was conducted (Figures 1,2), revealing a cystic mass in the left pelvis, measuring 92x71x112 mm, as well as a smaller fluid-filled mass originating from the appendix. No significant symptoms were reported, except for occasional self-limiting episodes of diarrhea in the previous 30 days, which did not require any medication. Subsequently, the patient was referred for surgical consultation. As she expressed a firm desire for pregnancy, fertility-sparing surgery was offered, involving left adnexectomy, omentectomy and lymphadenectomy of the pelvis, obturator and lumbosacral nodes. Additional right ovary biopsy, multiple peritoneal biopsies, peritoneal washing, appendicectomy and resection of the appendicular neoformation were performed. The surgical procedure took place in December 2020. Histological examination revealed a MiNEN of the appendix, with a low-grade neuroendocrine component (G1 NET) in combination with a lowgrade appendiceal mucinous neoplasm (LAMN). The pathological stage was pT4 N0 M1 (according to the AJCC VIII ed.), as the tumor reached the visceral peritoneum, and none of the nineteen resected lymph nodes showed metastatic invasion. A single distant metastasis was histologically reported as a 2 mm nodule of the omentum with neuroendocrine characteristics. Tumour epithelial (CEA, CA19.9, CA50, CA15.3, CA125) and neuroendocrine (NSE, chromogranin) marker levels were measured in serum samples. NSE levels were slightly above the upper limit of the reference interval (19.3 ng/mL; upper limit of the reference interval: 18.3 ng/mL), whereas all the remaining markers were within the limits. Imaging reassessment by contrast-enhanced CT scan was performed after surgery and revealed two additional lesions suspicious for metastases. One was located in the spleen and had a polylobate appearance and irregular margins (Figure 3), and the other one was located between the right iliac vessels and ipsilateral psoas muscle and measured 21x15 mm (Figure 4). The case was discussed by our interinstitutional multidisciplinary neuroendocrine tumour board to evaluate the best management strategy. The board recommended surgical resection of the two suspicious nodules, followed by intraperitoneal intraoperative hyperthermia (HIPEC). Therefore, in September 2021, the patient underwent exploratory laparotomy, right adnexectomy, splenectomy, omentectomy, multiple peritoneal biopsies and resection of the falciform ligament. Histologic examination did not show presence of disease on the resection margins and confirmed the dual nature of the neoplasm, revealing LAMN infiltration of the spleen and a neuroendocrine origin of the iliac lesion. Mitomycin C was intraperitoneally administered (58.8 mg) as part of the HIPEC procedure. Since the neoplasm has two distinct biological components, namely, mucinous and neuroendocrine characteristics, HIPEC was tailored to the main component of the disease in-loco (LAMN). After 3 months, clinical and imaging re-evaluations were performed, revealing an exophytic neoformation (31x30 mm) between the stomach and the tail of the pancreas (Figure 5). In a subsequent 18FDG-PET scan, no pathological uptake of the radiotracer was detected, whereas a 68GA-edotreotide-PET scan revealed slight uptake. NSE levels were once again slightly above the upper limit of the reference interval (20.1 ng/mL; upper limit of the reference interval: 18.3 ng/mL). As disease relapse was suspected, the case was discussed again at the Neuroendocrine Tumour Board, which proposed surgical biopsy of the newly found lesion to determine its origin and offer the patient tailored systemic treatment. Nevertheless, surgical biopsy was deemed unfeasible due to its location and size. Therefore, systemic treatment was selected based on the predominant histologic component of the main lesion after external review of the examination that confirmed the initial diagnosis. Since LAMN was the main component of the pelvic mass removed first, the patient was prescribed fluoropyrimidinebased chemotherapy, but she refused intravenous administration and requested oral treatment. Therefore, treatment with 1500 mg of capecitabine per day 2 weeks on/1 week off was started in September 2021. Additionally, given the positive results shown by 68GAedotreotide-PET scan, the patient was prescribed a long-acting somatostatin analogue (SSA-LAR) by intramuscular administration (30 mg every 28 days). Imaging re-evaluations were performed every 4 months during follow-up. The last whole-body contrast-enhanced CT scan was performed in January 2024 (Figure 6), showing dimensional shrinkage of the known lesion (24x19 mm vs 31x30 mm). Within twenty-eight months of treatment with a combination of capecitabine and SSA-LAR, no new lesions were found, and no dimensional increase in the known lesion was observed. The patient remained asymptomatic and in excellent clinical condition, although her desire for a pregnancy could not be fulfilled.

Figure 1: Contrast-enhanced MRI evidences a cystic mass in the left pelvis, measuring 92x71x112 mm.

Figure 2: Contrast-enhanced MRI evidences a suspicious fluid-filled lesion originating from the appendix.

Figure 3: Contrast-enhanced CT scan shows a suspicious lesion in the spleen, with polylobate appearance and irregular margins.

Figure 4: Contrast-enhanced CT-scan shows a suspicious lesion localized between the right iliac vessels and ipsilateral psoas muscle, measuring 21x15 mm.

Figure 5: Contrast-enhanced CT scan, performed 3 months after pelvic surgery and HIPEC, shows an exophytic neoformation measuring 31x30 mm between the stomach and the tail of pancreas, suspicious for disease relapse.

Figure 6: The latest whole-body contrast-enhanced CT scan performed by the patient, showing disease control and dimensional reduction of the known site of disease (24x19 vs 31x30 mm) within 2 years of treatment combining capecitabine and SSA-LAR.